Genetic studies first established that ras p21 proteins require a defined carboxy-terminal structure to exert their biological function. This structure, known as the CAAX box, consists of a conserved cysteine residue located at position 186 (except in the K-ras4B p21 protein, in which cysteine is located at position 185), two aliphatic amino acids and any carboxy-terminal amino acid residue. Mutations affecting the basic CAAX box structure of oncogenic ras p21 proteins completely abolish their transforming activity, presumably by impeding their interaction with the inner side of the plasma membrane. Such interaction requires a series of post-translational modifications within the CAAX box motif which include (a) farnesylation of the Cys.sup.186 residue; (b) cleavage of the three carboxy-terminal amino acid residues; and (c) methylation of the free carboxyl group generated in the resulting carboxy-terminal farnesyl-cysteine residue. The interaction of these farnesylated ras p21 proteins with cellular membranes is further strengthened by palmitoylation of neighboring upstream cysteine residues. See Hancock, et al., Jun. 30, 1989, Cell 57: 1167-1177; and Casey, et al., November 1989, Proc. Natl. Acad. Sci. U.S.A. 86: 8323-8327.
Recent studies have suggested that the donor of the farnesyl residue present in ras p21 proteins is likely to be FPP, a precursor in the biosynthesis of cholesterol. Treatment of S. cerevisiae cells or Xenopus oocytes with inhibitors of HMG-CoA reductase, the enzyme responsible for the synthesis of mevalonic acid, the precursor of isoprenoid compounds, blocks the function of ras proteins in these cells. These results have raised the possibility of using available inhibitors of cholesterol biosynthesis to block neoplastic transformation induced by ras oncogenes. See, Schafer, et al., Jul. 28, 1989, Science 245: 379-385; and Goldstein and Brown, Feb. 1, 1990, Nature 343: 425-430. However, FPP is not only an intermediate in the biosynthesis of cholesterol, but also a precursor of ubiquinones, dolichols and Haem A. Therefore, it is likely that attempts to block ras oncogene function by inhibiting the synthesis of FPP will cause major disruptions in other cellular pathways. For a review, see Touchette, April 1990, J. NIH Res. 2: 61-65.